General principles of cancer pain relief
Pain is a common symptom of cancer with a huge impact on quality of life. Patients are forced to fight the fear of death while undergoing the physiological and psychological torture induced by pain. Fortunately, recent advances have made it far easier to deal with cancer-related pain. Cancer-related pain can be caused by a tumor compressing or infiltrating nearby body parts, as in the pathologic fractures caused by bone metastasis. Pain is also induced through chemotherapy or radiotherapy-induced inflammation of the mucous membranes. A pain scale has been devised to assess the level of pain from 0 to 10. A score of 1-3 indicates a complete lack of pain or only mild pain; a score of 4 to 6 indicates moderate pain; and 7 to 10 indicates severe pain. According to recommendations by the WHO, different levels of pain should be dealt with differently. Mild pain can be dealt with using nonsteroidal anti-inflammatory drugs (NSAID) or paracetamol. Moderate pain is usually treated using weak opioids, such as codeine or tramado. Severe pain requires strong opioids, such as a fentanyl transdermal patch or morphine. These drugs can be delivered orally, transdermally, or via other non-invasive methods. Intravenous injection can be used to provide rapid relief from pain. In approximately 80-90% of cases, cancer-related pain can be controlled using adjuvant drugs in accordance with the above principles. Unfortunately, opioid administration induces side effects, including nausea, vomiting, drowsiness, pruritus, urinary hesitancy, and even respiratory depression, and/or unconsciousness. Furthermore, patients tend to develop tolerance to the drugs, and therefore periodically require an increase in dosage to feel the same level of effect.
 

Definition of intractable cancer pain and treatment
In approximately 10-20% of cancer cases, the pain cannot be relieved through the oral or transdermal administration of drugs, or the patient is unable to tolerate the side effects. These situations are referred to as intractable cancer pain. These patients require advanced invasive analgesic therapy, which can be divided into two categories. One category involves blocking or interfering with the pain message transmitted from tissue to the brain, known as nerve block or neuroablative procedure. The other category involves the delivery of opioids directly into the spinal cavity (so-called intraspinal drug delivery system) in order to avoid systemic side effects caused by drug administration.
 

• Neuroablation procedures

1. Nerves are blocked using drugs (such as pure alcohol or phenol) or radiofrequency ablation to induce permanent damage to targeted nerves, as opposed to the temporary blocking induced by local anesthetics.
2. Neuroablative procedures cannot be applied indiscriminately. There must be an appropriate target; i.e., visceral pain induced by pancreatic cancer can be relieved by destroying the splanchnic plexus, which dominates the abdominal organs. The application of neuroablative procedures to the spinal cord or brain, such as cordotomy and hypophysectomy, have proven ineffectual and excessively destructive, and are therefore rarely used.
3. Neuroablative procedures targeting the aorta, inferior vena cava, and spinal perimeter are prone to complications. Patients must carefully assess their own prognosis, and associated risks and benefits before undergoing neuroablative procedures.
4. All neuroablative procedures can be viewed as image-guided minimally invasive surgery, aimed at maximizing the analgesic effects while minimizing the amount of damage. Routine neuroablative procedures are performed under fluoroscopic/ultrasound double image-guidance in conjunction with a nerve stimulator to locate and thereby avoid damage to important nerves. This process is outlined in Figure 1.
5. The neuroablative approach is not a panacea that eliminates the need for pain medication. It should be considered a supplementary analgesic therapy of limited effect. For example, destroying only the sympathetic plexus to block the visceral sensations along the splanchnic nerve is effective in relieving dull pain or pain caused by pancreatic cancer. However, metastasis into the abdominal wall causes somatic pain, which cannot be relieved by blocking visceral nerves. Such cases require painkillers or damage to the somatic nerve. The analgesic effects of nerve blockage are not permanent. The effects of neuroplasticity and nerve regeneration can lead to the recurrence of pain, sometimes at elevated levels. It is common that the alleviation of major pain brings to the forefront the irritation caused by minor pain.
    

In the following, we present an introduction to neuroablative procedures for intractable cancer pain caused by thoracic and abdominal tumors.
 

Thoracic nerve
In cases of pleural or rib metastasis (Figure 2), patients are prone to chest wall syndrome involving somatic pain as well as visceral pain. Some patients endure a burning sensation throughout the body, whereas other patients feel a tearing sensation with every breath and cough. When the analgesic effect of drugs declines, pain can be relieved by blocking intercostal nerve(s); however, this commonly leads to pneumothorax. Following image-guided paravertebral neurolysis, a needle is maneuvered close to the pravertebral space (Figure. 3) using ultrasound and fluoroscopic guidance (Figure. 4). A high concentration of alcohol or phenol is then injected to destroy the intercostal nerve and sympathetic nerve simultaneously with the aim of blocking both somatic and visceral pain. Epidural alcohol injection is used in cases where lesions appear close to the spine or clearly violate the neural foramen compressing the intercostal nerve (Figures 5 and 6). Following the injection of a developer to confirm that the drug covers most of the affected area, a high concentration of alcohol is injected to destroy the tumor-invaded dorsal root ganglia.
 

Celiac plexus block
Celiac plexus blockage is a common neuroablative procedure that has proven highly effective in improving the quality of life of terminal cancer patients. The visceral sensory nerve dominating the abdominal organs transmits visceral pain to the spinal cord along both sides of the T5 to T12 sympathetic nerves. The T5 to T9 sympathetic nerves converge to the greater splanchnic nerve, T10 and T11 form the lesser splanchnic nerve, and T12 separately forms the leasts planchnic nerve. The complex splanchnic nerves pass through the diaphragm to form the celiac plexus surrounding the aorta and celiac trunk, at which point the neuron body becomes the celiac ganglion (Figure 7). Traditionally, celiac plexus block is used to relieve intractable pain from organs of the upper abdominal, such as the visceral pain caused by cancers of the stomach, pancreas, liver, and cholangiocarcinoma with liver metastasis, para-aortic lymph node metastasis, and cancerous peritonitis. The injection of alcohol at high concentrations is used to perform celiac plexus block under CT-guidance, as shown in Figure 8. However, tumor invasion can distort anatomical structures and thereby alter the relative position of nerves. Blocking the plexus in front of the aorta has poor analgesic effect for deep abdominal pain and upper back pain caused by aortic lymph node metastasis (Figure. 9). Thus, bilateral splanchnic neurolysis is currently used as an alternative to celiac plexus block. Patients lie face-down as radiofrequency electrocautery probes are guided by X-ray and ultrasound into the visceral plexus (typically at T11 and T12 vertebral body side) (Figure. 10). Electric stimulation is used to locate the nerves, and anesthetic is injected to numb the area. Radiofrequency ablation is then applied to the targeted nerves (as shown in Figure 11), followed by the injection of high concentrations of alcohol to destroy the splanchnic plexus, as indicated in Figure 12. It has been shown that this treatment has an analgesic effect on 80-90% of peritoneal cancer patients. Many patients undergo severe constipation prior to nerve blockage due to the extensive use of opioid drugs. Splanchnic nerve block deals with the sympathetic nerve, which can lead to slight diarrhea, which can be regarded as an additional therapeutic effect. Superior hypogastric plexus block can relieve pain caused by pelvic tumors, and ganglion impar block can facilitate the management of perineal pain.
 

Intraspinal drug therapy
Oral opioids enter the bloodstream via the gastrointestinal tract before being transported to the central nervous system. Thus, oral opioids can lead to numerous gastrointestinal complications, such as severe constipation, which limits drug dosages. Pharmacological studies have shown that the intravenous administration of morphine is approximately three times as powerful as oral morphine as an analgesic. The efficacy of morphine delivered to the epidural space is thirty times as powerful as oral morphine, and the infusion of morphine directly into the spinal cavity is three hundred times as powerful. The most important benefit of intraspinal administration is the reduced likelihood of gastrointestinal complications, such as nausea, vomiting, and constipation, making it ideal for patients who cannot tolerate the side effects of opioids. Prior to intraspinal administration, it is necessary to consider the expected survival of patients to determine whether to implant permanent devices. In principle, a temporary catheter can be inserted for patients with a prognosis of less than three months. Patients expected to survive more than three months tend to be given an intrathecal morphine pump or intrathecal drug delivery system.

Epidural drug infusion: The immune response in the intrathecal space is weak; therefore, a temporary catheter is implanted into the epidural space near the area of greatest pain under image guidance to reduce the risk of infection along the central nervous system. As shown in Figure 13, the implantation of an epidural catheter in a gastric cancer patients enables the uniform spreading of drugs to the both sides of the epidural space, thereby covering the T4 to T11 areas, for the infusion of morphine. The CT scan in Figure 14 shows the catheter in the epidural space. Generally, a temporary catheter can be used for approximately two to four weeks.

Intrathecal morphine pump: For patients with intractable cancer pain who are expected to survive more than three months, epidural morphine infusion can reduce 50-70% of the pain within a short period of epidural morphine infusion (approximately one week). The implantation of a permanent pump for long-term pain treatment can also be considered. Intrathecal morphine infusion therapy involves the image-guided implantation of a permanent catheter into the intrathecal space corresponding to the areas of greatest pain (Figure 15). Then the catheter is connected to a micro-pump implanted below the navel for the injection of morphine, as shown in Figures 16 to 18. Postoperative CT scanning can be used to ensure that the micro-pump is under the skin and the catheter is in the spinal cavity. The pump provides a specific dose of drugs, and can be controlled from outside the body. Morphine within the pump reservoir must be replaced or adjusted within 180 days according to the condition of the patient; however, this can be accomplished in vitro without the need to remove the pump. Patients need only return to the clinic for supplementary drugs and therefore do not need to self-administer any drugs. The analgesic effectiveness of this treatment has led to its widespread adoption in the U.S. and Europe. It has yet to be adopted in Taiwan.
 

Epilogue
Cancer patients are forced to fight the fear of death while undergoing the physiological and psychological torture induced by pain, directly undermining their quality of life and the time they spend with family. A range of treatments have been developed to treat cancer-related pain. Image-guided nerve blocking can be used to customize pain relief therapy to improve quality of life for patients.​